Methods for the preparation of hiv attachment inhibitor piperazine prodrug compound

ABSTRACT

A method for making the compound 
     
       
         
         
             
             
         
       
     
     is set forth utilizing the starting material

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. Ser. No. 13/760,526filed Feb. 6, 2013, now allowed, which claims the benefit of U.S.Provisional Application Ser. No. 61/596,362 filed Feb. 8, 2012, which isherein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to methods of making HIV attachment inhibitorcompounds useful as antivirals, and in particular, to methods of makingthe piperazine prodrug compound identified as1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine.The invention also relates to the compounds, including intermediates,obtained by the processes herein set forth.

BACKGROUND OF THE INVENTION

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with tens of millions of people still infected worldwide at theend of 2011. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2005, for example,approximately 5.0 million new infections were reported, and 3.1 millionpeople died from AIDS. Currently available drugs for the treatment ofHIV include nucleoside reverse transcriptase (RT) inhibitors or approvedsingle pill combinations: zidovudine (or AZT or RETROVIR®), didanosine(or VIDEX®), stavudine (or ZERIT®) lamivudine (or 3TC or EPIVIR®),zalcitabine (or DDC or HIVID®), abacavir succinate (or ZIAGEN®),Tenofovir disoproxil fumarate salt (or VIREAD®), emtricitabine (or FTCor EMTRIVA®), COMBIVIR® (contains −3TC plus AZT), TRIZIVIR® (containsabacavir, lamivudine, and zidovudine), EPZICOM® (contains abacavir andlamivudine), TRUVADA® (contains VIREAD® and EMTRIVA®); non-nucleosidereverse transcriptase inhibitors: nevirapine (or VIRAMUNE®), delavirdine(or RESCRIPTOR®) and efavirenz (or SUSTIVA®), ATRIPLA®(TRUVADA®+SUSTIVA®), and etravirine, and peptidomimetic proteaseinhibitors or approved formulations: saquinavir, indinavir, ritonavir,nelfinavir, amprenavir, lopinavir, KALETRA®(lopinavir and Ritonavir),darunavir, atazanavir (REYATAZ®), and tipranavir (APTIVUS®), andintegrase inhibitors such as raltegravir (ISENTRESS®), and entryinhibitors such as enfuvirtide (T-20) (FUZEON®) and maraviroc(SELZENTRY®).

In addition, HIV attachment inhibitors are a novel subclass of antiviralcompounds that bind to the HIV surface glycoprotein gp120, and interferewith the interaction between the surface protein gp120 and the host cellreceptor CD4. Thus, they prevent HIV from attaching to the human CD4T-cell, and block HIV replication in the first stage of the HIV lifecycle. The properties of HIV attachment inhibitors have been improved inan effort to obtain compounds with maximized utility and efficacy asantiviral agents.

One HIV attachment inhibitor compound, in particular, has now shownconsiderable prowess against HIV. This compound is identified as1-(4-benzoyl-piperazin-1-yl)-2-[4-methoxy-7-(3-methyl-[1,2,4]triazol-1-yl)-1H-pyrralo[2,3-c]pyridine-3-yl]-ethane-1,2-dione,and is set forth and described in U.S. Pat. No. 7,354,924, which isincorporated herein in its entirety:

The above compound is the parent compound of the prodrug known as1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine.It is set forth and described in U.S. Pat. No. 7,745,625, which isincorporated by reference herein it its entirety. The compound isrepresented by the formula below:

Various methods for making this prodrug compound have been set forth,including those detailed in the '625 reference. In particular, the '625reference includes various methods for acylation, alkylation andphosphorylation. Another patent reference, U.S. Ser. No. 13/359,708filed Jan. 27, 2012, entitled “METHODS OF MAKING HIV ATTACHMENTINHIBITOR PRODRUG COMPOUND AND INTERMEDIATES”, also details variousprocedures for making the piperazine prodrug compound. These include amulti-step process which uses the compound

as a starting material, which is subsequently brominated, and thennitrated. Further on, a triazolyl moiety is added to the compound beforefurther attaching the piperazine moiety separated by dual carbonylgroups.

What is now needed in the art are new methods of making the piperazineprodrug compound which is useful against HIV. These methods shouldprovide a further comprehensive and efficient means for making theprodrug molecule, both in terms of overall yield and materialthroughput.

SUMMARY OF THE INVENTION

In a first embodiment, the invention provides a process for preparingthe compound of Formula I

which comprises:

-   (a) reacting the compound 1

with the acid chloride compound

-   to form the compound 2

and then

-   (b) contacting the compound 2 with a di-substituted amine (R²)₂NH in    base to produce the compound 3

and thereafter

-   (c) reacting the compound 3 with the dihydroxy compound

-   in acid solution, wherein the linker between the hydroxyl groups is    C₁-C₆ alkyl, to yield the compound 4

and

-   (d) reacting the compound 4 with the compound

-   in acid to produce the compound 5

-   (e) contacting the compound 5 with Me-X⁴ in base or MeO-R³ in acid    to produce the compound 6

and

-   (f) then performing an oxidation reaction on compound 6 using [O] to    yield the compound 7

and

-   (g) adding the triazolyl group

-   to compound 7, and then conducting a functional group    interconversion reaction, to obtain the compound (I) above, wherein:    -   R¹=—H, -Boc, -Piv, —SO₂Aryl, —CH₂SAryl, —CH₂OP(O)(OR)₂, —CH₂OR,        —CH₂Aryl;    -   R²=each independently —H, —CO₂R, —SO₂Aryl, —CHO;    -   R³ and R⁴=each independently —H, —CO₂R, —CH₂SR, —CH₂OR,        —CH(OR)₂, —CH(OR)(NR₂), —CH(NR₂)₂, (C₁-C₆) alkyl;    -   R=each independently —H, —C₁-C₆ alkyl, -aryl, —CH₂Aryl;    -   X¹=—H, —Cl, —Br, —I,

-   -   X²=—Cl, —Br, —I, —N(R²)₂, —OSO₂R;    -   X³=each independently —H, —OR, —NR₂ —Cl, —Br, —I, —SR, —SO₂R,        —SO₃R, —SR₂ ⁺;    -   and X⁴=—Cl, —Br, —I, OTs (tosylate group), +NR₃, -pyridium, and

In this embodiment, it is preferred that R¹ is —SO₂Aryl. Aryl herein ispreferably phenyl. It is also preferred that X¹ is —H. Additionally, itis preferred that X³ is —H. It is also preferred that the dihydroxycompound is ethylene glycol.

In a further embodiment, the invention is directed to a process forpreparing the compound of Formula I

which comprises:

-   (a) reacting the compound 1

with the acid chloride compound

-   to form the compound 2

and then

-   (b) contacting the compound 2 with a di-substituted amine (R²)₂NH in    base to produce the compound 3

and thereafter

-   (c) reacting the compound 3 with the dihydroxy compound

-   in acid solution, wherein the linker between the hydroxyl groups is    C₁-C₆ alkyl, to yield the compound 4

and

-   (d) reacting the compound 4 with the compound

-   in acid to produce the compound 5

-   (e) contacting the compound 5 with Me-X⁴ in base or MeO-R³ in acid    to produce the compound 6

and

-   (f) then performing an oxidation reaction on compound 6 using [O] to    yield the compound

and

-   (g) adding the triazolyl group 9

-   to compound 7, to obtain the compound (I) above wherein:    -   R¹=—H, -Boc, -Piv, —SO₂Aryl, —CH₂SAryl, —CH₂OP(O)(OR)₂, —CH₂OR,        —CH₂Aryl;    -   R²=each independently —H, —CO₂R, —SO₂Aryl, —CHO;    -   R³=—H, —CO₂R, —CH₂SR, —CH₂OR, —CH(OR)₂, —CH(OR)(NR₂), —CH(NR₂)₂;    -   R=each independently —H, —C₁-C₆ alkyl, -aryl, —CH₂Aryl;    -   X¹=—H, —Cl, —Br, —I,

-   -   X²=—Cl, —Br, —I, —N(R²)₂, —OSO₂R;    -   X³=each independently —H, —OR, —NR₂, Cl, —Br, —I, —SR, —SO₂R,        —SO₃R, —SR₂ ⁺;    -   and X⁴=—Cl, —Br, —I, -OTs, +NR₃, -pyridium, and

In this further embodiment, it is preferred that R¹ is —SO₂Aryl. Arylherein is preferably phenyl. It is also preferred that X¹ is —H.Additionally, it is preferred that X³ is —H. It is also preferred thatthe dihydroxy compound is ethylene glycol.

In another embodiment, there is provided a process for the preparationof the compound of Formula I

which comprises:

-   (a) reacting the compound 1

with the acid chloride compound

-   to form the compound 2

and then

-   (b) contacting the compound 2 with a di-substituted amine (R²)₂NH in    base to produce the compound 3

and thereafter

-   (c) reacting the compound 3 with the dihydroxy compound

-   in acid solution, wherein the linker between the hydroxyl groups is    C₁-C₆ alkyl, to yield the compound 4

and

-   (d) reacting the compound 4 with the compound

-   in acid to produce the compound 5

-   (e) contacting the compound 5 with Me-X⁴ in base or MeO-R³ in acid    to produce the compound 6

and then

-   (f) performing an oxidation reaction on compound 6 using [O] to    yield the compound 7

and

-   (g) performing an activation reaction to yield the resultant    compound 10

and then

-   (h) adding the triazolyl group 9

-   to compound 10 in the presence of Cu ion and a ligand to yield the    compound of Formula (I) above wherein:    -   R¹=—H, -Boc, -Piv, —SO₂Aryl, —CH₂SAryl, —CH₂OP(O)(OR)₂, —CH₂OR,        —CH₂Aryl;    -   R²=each independently —H, —CO₂R, —SO₂Aryl, —CHO;    -   R³=—H, —CO₂R, —CH₂SR, —CH₂OR, —CH(OR)₂, —CH(OR)(NR₂), —CH(NR₂)₂;    -   R=each independently —H, —C₁-C₆ alkyl, -aryl, —CH₂Aryl;    -   X¹=—H, —Cl, —Br, —I,

-   -   X²=—Cl, —Br, —I, —N(R²)₂, —OSO₂R;    -   X³ and X⁵=each independently —H, —OR, —NR₂, —Cl, —Br, —I, —SR,        —SO₂R, —SO₃R, —SR₂ ⁺;    -   and X⁴=—Cl, —Br, —I, -OTs, +NR₃, pyridium, and

-   -   The ligand is selected from the group of 1,2-diaminocyclohexane,        trans-1,2-diaminocyclohexane, cis-/trans-diaminocyclohexane,        cis-N,N′-dimethyl-1,2-diaminocyclohexane,        trans-N,N′-dimethyl-1,2-diaminocyclohexane,        cis-/trans-N,N′-dimethyl-1,2-diaminocyclohexane,        1,2-diaminoethane, N,N′-dimethyl-1,2-diaminoethane,        1,10-phenanthroline, 4,7-diphenyl-1,10-phenantroline,        5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenantroline, and        5-nitro-1,10-phenanthroline.        In this further embodiment, it is preferred that R¹ is —SO₂Aryl.        Aryl herein is preferably phenyl. It is also preferred that X¹        is —H. Additionally, it is preferred that X³ is —H.

Also provided herein is a method of making the compound of Formula II

which comprises:

-   (a) acylating the compound 10

using

to yield the compound 11

and then

-   (b) reacting compound 11 with compound 13

-   in an activation reaction to produce compound 14

and

-   (c) adding the triazolyl compound 9

-   in the presence of Cu ion and a ligand to obtain compound 15

and

-   (d) reacting compound 17

with compound 15 to produce compound 18

and

-   (e) conducting a functional group interconversion reaction to yield    the compound of Formula II above; wherein:    -   R⁵=—H, —OR, —NR₂, —Cl, —Br, —I, —SR;    -   R⁶=—H, -Boc, -Piv, —SO₂Aryl, —CH₂SAryl, CH₂OP(O)(OR)₂, —CH₂OR,        —CH₂Aryl, —Li, —Na, —K, —Ca, —Mg, TMG (Tetramethyl guanidine);    -   R=each independently —H, —C₁-C₆ alkyl, -aryl, —CH₂Aryl;    -   X¹=—H, —Cl, —Br, —I,

-   -   X⁵=—H, —OR, —NR₂, —Cl, —Br, —I, —SR    -   X⁶=—H, —OR, —NR₂, —Cl, —Br, —I, —SR, —SO₂R, —SR₂ ⁺, —OSO₂R,        —OSO₃R;    -   and X⁷=—Cl, —Br, —I, —OSO₂R.        In this embodiment, the ligand may be selected as previously set        forth. It is also preferred that R=tert-butyl, R⁶ and X¹ are —H,        and R⁵ is —OMe. Aryl herein is preferably phenyl.

For a further embodiment of the invention, there is set forth processfor making the compound of Formula III

which comprises:

-   (1) reacting compound

-   with phthalic anhydride, H₂O₂ and dichloromethane to yield compound

and

-   (2) conducting a PyBrop bromination reaction by reacting compound ii    with PyBrop to prepare compound III,

wherein R⁷=—H, alkyl, aryl, —SO₂R, —C(O)OR, and —C(O)NR₂; andwherein R=—H, —C₁-C₆ alkyl, aryl, —CH₂Aryl; and further wherein PyBropis the peptide coupling reagent Bromo-tris-pyrrolidinophosphoniumhexafluorophosphate. Aryl herein is preferably phenyl.

In addition, the invention is also directed to a compound, includingpharmaceutically acceptable salts and mixtures thereof, which isselected from the group of:

The invention also is directed to a process for the production of thecompound

which comprises

-   (1) removal of the t-butyl groups from the compound

-   using a solvent in the presence of water to obtain the compound

and

-   (2) reacting the compound

-   with TRIS (tris(hydroxymethyl)aminomethane) and optionally a second    solvent to obtain the compound

According to this process, the first solvent is selected from the groupof carboxylic acid, NMP (N-methyl-2-pyrrolidone), DMSO, MeCN, MeOH, andacetone. The acid is selected from the group of H₂SO₄, HNO₃, HCl,phosphoric and carboxylic acids. The second solvent is selected from thegroup of water, alkyl ketone, heptane, toluene, ethyl acetate, DMSO,MeCN, MeOH and acetone. Even more preferably, the acid is acetic acid,and the second solvent is acetone.

The present invention is directed to these, as well as other importantends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Unless otherwise specifically set forth, many reagents have beenidentified herein by their commonly accepted letter abbreviations in theart for ease of reference.

In addition, unless otherwise specifically set forth elsewhere in theapplication, the following terms may be used herein, and shall have thefollowing meanings:

An “alkyl” group refers to a saturated aliphatic hydrocarbon includingstraight chain and branched chain groups. Preferably, the alkyl grouphas 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, isstated herein, it means that the group, in this case the alkyl group maycontain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to andincluding 20 carbon atoms). More preferably, it is a medium size alkylhaving 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having1 to 4 carbon atoms. The alkyl group may be substituted orunsubstituted.

The term “C₁₋₆ alkyl” as used herein and in the claims means straight orbranched chain alkyl groups with up to and including 6 carbon atoms,such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,amyl, hexyl and the like.

An “aryl” “Aryl” or “Ar” group refers to an all carbon monocyclic orfused-ring polycyclic(i.e., rings which share adjacent pairs of carbonatoms) groups having a completely conjugated pi-electron system.Examples, without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted.

In a preferred embodiment of the invention, the synthesis of thepiperazine prodrug compound can be set forth in the following flowdiagram:

Even more preferably, as further set forth below, the synthesis of thepiperazine prodrug compound begins from the N-sulfonylated pyrrole 1a.Friedel-Crafts acylation with 2-chloro acetyl chloride, in the presenceof aluminum trichloride, provides the 3-acryl pyrrole derivative 2a.Displacement of the 2-choro ketone by the sodium salt of the N-formylsulfonamide, in the presence of a tetraalkylammonium halide, preferablybromide, preferably tetrabutylammonium bromide, provides theamino-ketone 3a. Ketal protection of the ketone, in the presence ofglycol and acid, results in the cleavage of the N-formyl protectinggroup and formation of the desired dioxalane 4a. A Pictet-Spenglercyclization with a formaldehyde equivalent, catalyzed by acid, providesthe ketone 5a, which is treated with trimethyl orthoformate (TMOF) andacid in the presence of a radical initiator such as AlBN or cumenehydroperoxide to give the 6-azaindole 6a. Oxidation of the pyridinenitrogen provides the N-oxide 7a which is then treated with PyBrop inthe presence of base, which brominates the C7-position, yielding thebromo-azaindole 8a after hydrolysis of the sulfonyl protecting group. Asecond Friedel-Crafts acylation onto C3 of the indole provides theoxalate 9a, which is coupled with the N-benzoyl piperazine to give theamide 10a. Addition of the triazole is catalyzed by copper, in thepresence of an appropriate ligand and base, to give the indole 11c whichis isolated as its lithium salt (or optionally as a co-salt with KBr).Alkylation of the indole nitrogen with the chloro-phosphate 14a givesthe phosphate ester 12a, and subsequent solvolysis of the tert-butylgroups provides the final compound 13a.

Thus, the production of the piperazine prodrug compound may be shownmore precisely as follows:

The foregoing description is merely illustrative and should not beunderstood to limit the scope or underlying principles of the inventionin any way. Indeed, various modifications of the invention, in additionto those shown and described herein, will become apparent to thoseskilled in the art from the foregoing description and examples. Suchmodifications are also intended to fall within the scope of the appendedclaims.

What is claimed is:
 1. A process for the production of the compound

which comprises (1) removal of the t-butyl groups from the compound

using a first solvent in the presence of water to obtain the compound

and (2) reacting the compound

with TRIS and optionally a second solvent to obtain the compound


2. The process of claim 1, wherein said first solvent is selected fromthe group of NMP, DMSO, MeCN, MeOH, acetone and a carboxylic acid. 3.The process of claim 1, wherein said second solvent is selected from thegroup of an alkyl ketone, heptane, toluene, and ethyl acetate.
 4. Theprocess of claim 1, wherein the first solvent is acetic acid, and saidsecond solvent is acetone.